Mysterious Hawaii Liver Disease Case ¢â‚¬â€œ Naproxen Overdose...

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  • Central Journal of Liver and Clinical Research

    Cite this article: Teschke R, Schulze J, Eickhoff A, Wolff A, Frenzel C (2015) Mysterious Hawaii Liver Disease Case – Naproxen Overdose as Cause Rather than OxyELITE Pro? J Liver Clin Res 2(2): 1013.

    *Corresponding author Rolf Teschke, Department of Internal Medicine II, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany, Tel: 49-6181-21859; Fax: 49-6181- 2964211; Email:

    Submitted: 08 May 2015

    Accepted: 05 June 2015

    Published: 08 June 2015

    Copyright © 2015 Teschke et al.


    Keywords • Hawaii liver disease mystery • Disease cluster • Naproxen • OxyELITEPro • Dietary supplements

    Review Article

    Mysterious Hawaii Liver Disease Case – Naproxen Overdose as Cause Rather than OxyELITE Pro? Rolf Teschke1*, Johannes Schulze2, Axel Eickhoff1, Albrecht Wolff3 and Christian Frenzel4 1Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Teaching Hospital of the Goethe University, Germany 2Institute of Industrial, Environmental and Social Medicine, Medical Faculty, Goethe University Frankfurt/Main, Germany 3Department of Internal Medicine II, Division of Gastroenterology, Hepatology and Infectious Diseases, Friedrich Schiller University Jena, Germany 4Department of Medicine I, University Medical Center Hamburg Eppendorf, Germany


    A liver case was reported from a Honolulu medical center in 2013 and remained mysterious due to poorly documented case details and conflicting statements, necessitating a reanalysis of medical files containing redacted raw data of the female patient described as previously healthy. This actual reanalysis provides evidence of a patient with a remarkable multimorbidity associated with a significant present and past history of multimedication by abundant potentially hepatotoxic synthetic drugs and by some dietary supplements [DS]. Her liver disease now is best explained as recurrent toxic hepatitis by overdosed naproxen, a non-steroidal antiinflammatory drug [NSAID] with a well known and significant hepatotoxic potency. Actually, its reuse - five months after first disease onset - to treat daily headaches for a month unexpectedly caused a recurrence of the scleral icterus as at the initial onset. Additional diagnoses now include DILI by other used synthetic drugs; symptomatic acute acalculous cholecystitis associated with gallbladder sludge; acute hepatitis, preferentially prior not excluded hepatitis E virus infection, infections by HSV and VZV; and nonalcoholic fatty liver disease. Evidence is lacking that any of the four used DS was the culprit, including OxyELITE Pro [OEP] that initially was incriminated as the sole cause of liver disease by a team of investigators in Hawaii. The conclusion is reached that the case now loses its mystery and is best explained by overdosed naproxen, a NSAID with a known history of hepatotoxicity - rather than by any DS including OEP - affecting a multimorbid and multimedicated patient.

    ABBREVIATIONS ADHD: Attention Deficit Hyperactivity Disorder; ALP: Alkaline

    Phosphatase; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; BMI: Body Mass Index; CDC: Centers for Disease Control and Prevention; CIOMS: Council for International Organizations of Medical Sciences; CMV: Cytomegalovirus; DILI: Drug induced Liver Injury; DS: Dietary Supplement; EBV: Epstein Barr Virus; FDA: Federal Drug Administration in Washington DC, USA; HAV: Hepatitis A Virus; HBc: Hepatitis B core; HBs: Hepatitis B surface; HBV: Hepatitis B Virus; HDS: Herbal Dietary Supplement; HCV: Hepatitis C Virus; HEV: Hepatitis E Virus; HSV: Herpes Simplex Virus; HILI: Herb induced Liver Injury; LFTs: Liver Function Tests; N: Normal range as multiple of its upper limit; NAFLD: Non-alcoholic Fatty Liver Disease; NSAID: Non- Steroidal Anti-inflammatory Drug; OEP: OxyELITE Pro; PCP:

    Primary Care Provider; PCR: Polymerase Chain Reaction; R: Ratio; RUCAM: Roussel Uclaf Causality Assessment Method; VZV: Varicella Zoster Virus.

    INTRODUCTION Dietary supplements [DS] may be effective when used as

    slimming aids, but there is considerable concern regarding rare side effects including liver injury possibly attributable to few DS products [1-7]. In this context, the Centers for Disease Control and Prevention [CDC] published a preliminary report on a liver disease cohort of seven patients that emerged in Hawaii in the summer 2013 and remained a mystery [8]. This created uncertainty due in part to the reporting of inconsistent and incomplete data, associated with the lacking of an ascertained culprit. However, an assumed temporal association initially focused on OxyELITE Pro

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    J Liver Clin Res 2(2): 1013 (2015) 2/13

    [OEP], a popular over-the-counter DS intended for weight loss and muscle building, which was suspected as a single causative product for all patients of this unique disease cluster. A final CDC report has not yet been published, presumably due to continued uncertainties and ongoing scientific or regulatory investigations and discussions. Occurrence of this Hawaii liver disease cluster in primarily summertime is suggestive of a seasonal outbreak by some type of hepatitis infections, including hepatitis A or E [9], which so far might not have been excluded with the required scrutiny. It is also well recognized that patients taking herbal dietary supplements [HDS] tend to use these in overdoses and are under medication by several synthetic drugs and additional HDS, conditions considered as confounders [10-12].

    Subsequently, another liver case of assumed connection with OEP use was reported, but some peculiarities and suspected confounders prevailed, questioning the proposed causal relationship a priori [13]. Actually, this case was characterized by a mild clinical course, absence of encephalopathy, only moderately elevated aminotransferases, virtually normal bilirubin values, and a hepatocellular rather than a cholestatic type of injury; complete recovery was surprisingly prolonged and only achieved within 85 days, whereas short-term restoration is to be expected under these favourable clinical conditions [13]. This called for additional intensified searches on alternative culprits to explain the liver disease, which initially was attributed to OEP with a highly probable causality [13] using the CIOMS scale [Council for International Organizations of Medical Sciences], also named RUCAM [Roussel Uclaf Causality Assessment Method] [14]. This unusual high causality grading is rarely awarded for assumed hepatotoxicity cases [15], unless case conditions were virtually perfect with fulfilment of all key CIOMS criteria, complete lack of confounders including comedication, and valid exclusion of alternative causes such as hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV], hepatitis E virus [HEV], and infections by cytomegalovirus [CMV], Epstein Barr virus [EBV], herpes simplex virus [HSV], and varicella zoster virus [VZV], just to name a few examples [15-18]. In addition, this patient was not healthy as erroneously claimed [13]; prior to OEP use, she likely had morbid obesity and associated diseases including a metabolic syndrome, specifically with a hepatic metabolic syndrome and non-alcoholic fatty liver disease [NAFLD]. These conditions are well known risk factors for drug-induced liver injury [DILI] [19,20]. Morbid obesity often is associated with painful musculoskeletal disorders requiring management of the chronic multipain syndrome by synthetic drugs, mostly non- steroidal antiinflammatory drugs [NSAID] with their known hepatotoxic potency [21].

    In face of these obvious uncertainties, the raw data of this complex case were reanalyzed for types of used DS products including their possible temporal associations, validity of presented case information, overall case data quality, confounding variables, complete exclusion of alternative causes, comorbidity, comedication, and firm causal attribution. The actual evaluation of this case follows recently published recommendations [15,22- 24]. Due to lack of a valid diagnostic biomarker, the diagnosis of DILI and herb-induced liver injury [HILI] is a diagnosis of exclusion [24]. Our analysis now shows that naproxen used in overdose rather than OxyELITE Pro is the most likely cause of

    this initially mysterious Hawaii liver disease case, affecting a multimorbid and multimedicated female patient.

    APPROACHES OF CASE DATA ANALYSIS Redacted files of the patient’s medical records were analyzed

    for case data consistency, completeness of alternative cause exclusion, medication by synthetic drugs, use of DS, temporal association, clinical confounders, and causality assessment. The overall aim of this case analysis was to retrieve additional case data to clarify the possible culprit(s) of this mysterious liver disease [13]. Actual methods of analytical approaches were similar to those applied in previous assessments of HILI and DILI cases [15,22-24].

    CASE NARRATIVE For an initial overview, some case details are extracted from

    the original but redacted medical files and summarized as short narrative (Table 1) and as tabular list (Table 2). This approach facilitates a comparative analysis of the case data derived from the original files with those already published [13].

    This female patient was described as 35 years old and healthy in the published report [13], but the publicized clinical statement on her health condition was in no way corroborated by the f